Fos related antigen 1 (Fra-1) is a component of the dimeric AP-1transcription factor that plays an important role in both cell cycle regulation andcancer initiation and progression. Fra-1 is highly increased in invasive types ofbreast cancer, e.g. MDA-MB-231 cells, when compared to the noninvasive types.Furthermore, Fra-1 in normal fibroblasts show a strictly regulated pattern ofexpression during G0 to G1 transition in response to growth factors.My thesis research focused on the significance of the excessively high levelsof Fra-1 in serum starved MDA-MB-231 cells, and how this phenomenon ismaintained in absence of any external stimuli? To answer this question, wecharacterized the pattern of expression of Fra-1 and other AP-1 family members asa function of cell cycle in invasive breast cancer cell lines, and compared them tonon-invasive and normal cells. One of the major results we observed was theexcessive levels of Fra-1 produced by MDA-MB-231 under serum starvation andits maintenance all-through the cell cycle. Also, we identified a role for Fra-1 inkeeping MDA-MB -231 cells growing, albeit very slowly.Additionally, we explored different properties of Fra-1 in MDA-MB-231. Ourwork showed that Fra-1 is increased in this cell line due to both increasedexpression and stability. In addition, we found Fra-1 in MDA-MB-231 cells to be both nuclear and cytoplasmic in distribution which was contrary to what was foundbefore in normal cells where Fra-1 is solely nuclear.Furthermore, we utilized A-Fos, a dominant negative form of Fra-1, to testthe role of AP-1 in maintaining the oncogenic and metastatic properties of MDA-MB-231cells. We found that A-Fos completely suppressed the ability of MDA-MB-231 cells to grow on agar. In addition, it attenuated the migration of these cells.A further major finding of our work demonstrated an ability of MDA-MB-231cells to secrete in their medium some factors(s) that can induce Fra-1, as tested inMCF10A maintained in serum free medium. We found that both the MEK/ERK andMLK mediated pathways are involved in this process. These secreted factors werefound to have a significant role in controlling migration and proliferation ofneighboring cells, an effect that was mediated through Fra-1. Furthermore, byinserting A-Fos in MDA-MB-231 cells we were able to show that the control of suchsecretion of these substances is mediated through Fra-1. The ability of these factorsto self-control MDA-MB-231 cells is yet to be tested.Lastly, we extended these results to invasive cancers from other tissueorigins, e.g. prostate and colon cancers, suggesting a universal role of Fra-1 ininvasive cancers.
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